September 17, 2003
Anemia, defined as a reduction below normal in the number of red blood cells or quantity of hemoglobin, has long been recognized as an important clinical problem in HIV disease. It remains the most frequent blood-related complication in people living with HIV, and can cause a myriad of symptoms, including fatigue, shortness of breath, rapid heartbeat, paleness, headaches, decreased sex drive, exercise intolerance and inability to concentrate.
Early in the epidemic, AZT (zidovudine, Retrovir), the first antiretroviral agent to win FDA approval, was found to have anemia as a common adverse side effect. In the late '80s and early '90s, treatment of anemia with a blood transfusion was noted to be associated with a significant decrease in survival in patients with HIV/AIDS. Subsequently, recombinant human erythropoietin (epoetin alfa, Procrit) was approved as an alternative treatment option for anemic HIV-positive patients taking AZT. Clinical studies have shown that anemia -- in this patient population -- adversely affects functional ability and quality of life. In addition, there is evidence that anemia is associated with decreased survival.
HAART (highly active antiretroviral therapy) was introduced into clinical practice in 1996, and has had a profound impact on the clinical course of HIV disease, significantly slowing disease progression, reducing mortality and improving the long-term prognosis for many patients. In the HAART era, anemia has been perceived by many to be a less significant clinical issue. While recent data suggest severe anemia is indeed less frequent, mild to moderate anemia has remained a common abnormality among HIV-positive individuals receiving HAART. In general, anemia is more prevalent among HIV-positive women than men, in those with CD4 cell counts less than 200, and in African-Americans.
Observational studies have also suggested that recovery from anemia is associated with improved survival. In addition, well-controlled clinical trials have demonstrated that increasing hemoglobin levels in HIV-positive patients with mild to moderate anemia enhances quality of life and improves physical well-being. Together, these findings emphasize the continuing importance of monitoring HIV-positive patients for anemia and maintaining normal hemoglobin levels as a treatment goal, even as antiretroviral therapy continues to improve.
Initial controlled clinical trials showed that epoetin alfa (Procrit) administered three times weekly was safe and effective in correcting anemia, reducing blood transfusions, and improving quality of life and physical well-being in HIV/AIDS patients receiving AZT. More convenient dosing regimens have subsequently been investigated. Once-weekly dosing of 40,000 units was found to be as effective as thrice-weekly dosing among anemic HIV-positive patients in increasing hemoglobin levels and improving quality of life. The present study presents preliminary data evaluating epoetin alfa 40,000 units every two weeks for maintaining hemoglobin levels in anemic HIV-infected patients. The study was done to assess the efficacy and safety of a more convenient dosing regimen for HIV-positive anemic patients who are frequently burdened with complex medication regimens.
This is a 24-week, multi-center, open-label clinical trial in which HIV-positive patients with anemia (hemoglobin less than or equal to 12 g/dl) are given epoetin alfa (40,000 units subcutaneously) once per week until the anemia is corrected (hemoglobin greater than or equal to 13 g/dl). The patients are then switched to a maintenance phase during which the dosing interval of epoetin alfa is extended to every two weeks (40,000 units). If, during the maintenance phase, their hemoglobin drops to less than 11 g/dl, the patients are switched back to once-weekly dosing. If their hemoglobin is greater than or equal to 14 g/dl, the dosing is temporarily withheld until the hemoglobin decreases to less than 14 g/dl, at which time maintenance-phase dosing resumes.
At the time of this preliminary analysis, 120 patients were enrolled in the study and 94 (79 percent) had reached the target hemoglobin (greater than or equal to 13 g/dl). After reaching the target hemoglobin, 83 percent of the patients were able to maintain hemoglobin levels with the once-every-two-week (or less frequent) dosing schedule. The calculated median dosing interval for effective maintenance dosing was 40,000 units every 2.7 weeks. Epoetin alfa was very well tolerated, with only one adverse event (mild muscle spasms in the lower back) considered possibly related to epoetin alfa.
That anemia can be a serious condition among HIV-positive patients is widely accepted; however, what is not widely appreciated is how common anemia remains in the HAART era, particularly in women and patients of African-American descent. Fatigue and anemia are often overlooked and undertreated in patients with HIV infection. Perhaps this is due to the time constraints of HIV-treating physicians coupled with the increasing complexity of monitoring indices of viral activity and resistance. This lack of attention to anemia and its common symptom -- fatigue -- is particularly startling given the importance HIV-positive patients place on them. Surveys have shown patients consistently rank fatigue among the worst side effects they have experienced. In the same surveys, physicians reported fatigue as one of the least significant consequences of HIV and HIV therapy.
Treating anemia in patients with chronic illnesses, including HIV disease, has been demonstrated to reduce transfusion requirements, enhance functional performance, and improve physical, as well as psychological, quality of life. In addition, it is associated with increased survival. Blood transfusions may be appropriate for the treatment of acute anemia in certain circumstances, but their use should be minimized due to the risks of transmission of viral infections, immunosuppression and other hazards. The cause of anemia in HIV infection is often multi-factorial; however, in most cases, it is responsive to epoetin alfa. Epoetin alfa has an excellent safety record and the present study suggests longer dosing intervals are effective in maintaining hemoglobin levels.
Medication dosing convenience is intimately linked to adherence. Consequently, a more convenient, equally efficacious regimen for patients would be expected to improve compliance. Medication regimens for patients with HIV disease frequently remain complex and rigorous, even in the era of HAART. Any improvement in dosing convenience should be warmly welcomed by both prescribing physicians and people living with HIV/AIDS. The longer dosing intervals of epoetin alfa will have significant beneficial cost implications as well. As we await a final analysis of these data, this preliminary analysis is encouraging on all fronts.
Read the poster of the abstract covered in this article.
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